Direct myosin-2 inhibition enhances cerebral perfusion resulting in functional improvement after ischemic stroke
| Autor: | András Málnási-Csizmadia, Ivan Ivic, Demeter Túrós, Domokos Máthé, Anna Á. Rauscher, Gabriella Pál, Peter Toth, Máté Pénzes, Árpád Dobolyi, Nikolett Hegedűs, Krisztián Szigeti, Parasuraman Padmanabhan, Máté Gyimesi |
|---|---|
| Přispěvatelé: | Lee Kong Chian School of Medicine (LKCMedicine), Cognitive Neuroimaging Centre |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Contraction (grammar) Medicine (miscellaneous) Vasodilation myosin Brain Ischemia Constriction 03 medical and health sciences 0302 clinical medicine Internal medicine Myosin medicine Animals Medicine [Science] Rats Wistar Cerebral perfusion pressure Thrombus Pharmacology Toxicology and Pharmaceutics (miscellaneous) smooth muscle cell Tomography Emission-Computed Single-Photon business.industry Infarction Middle Cerebral Artery Blood flow medicine.disease Magnetic Resonance Imaging reperfusion Rats Stroke Disease Models Animal 030104 developmental biology Cerebral blood flow SPECT Cerebrovascular Circulation Reperfusion Cardiology Rabbits MCAO business 030217 neurology & neurosurgery Research Paper |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| DOI: | 10.7150/thno.42077 |
| Popis: | Acute ischemic stroke treatment faces an unresolved obstacle as capillary reperfusion remains insufficient after thrombolysis and thrombectomy causing neuronal damage and poor prognosis. Hypoxia-induced capillary constriction is mediated by actomyosin contraction in precapillary smooth muscle cells (SMCs) therefore smooth muscle myosin-2 could be an ideal target with potentially high impact on reperfusion of capillaries. Methods: The myosin-2 inhibitor para-aminoblebbistatin (AmBleb) was tested on isolated human and rat arterioles to assess the effect of AmBleb on vasodilatation. Transient middle cerebral artery occlusion (MCAO) was performed on 38 male Wistar rats followed by local administration of AmBleb into the ischemic brain area. Development of brain edema and changes in cerebrovascular blood flow were assessed using MRI and SPECT. We also tested the neurological deficit scores and locomotor asymmetry of the animals for 3 weeks after the MCAO operation. Results: Our results demonstrate that AmBleb could achieve full relaxation of isolated cerebral arterioles. In living animals AmBleb recovered cerebral blood flow in 32 out of the 65 affected functional brain areas in MCAO operated rats, whereas only 8 out of the 67 affected areas were recovered in the control animals. Animals treated with AmBleb also showed significantly improved general and focal deficit scores in neurological functional tests and showed significantly ameliorated locomotor asymmetry. Conclusion: Direct inhibition of smooth muscle myosin by AmBleb in pre-capillary SMCs significantly contribute to the improvement of cerebral blood reperfusion and brain functions suggesting that smooth muscle myosin inhibition may have promising potential in stroke therapies as a follow-up treatment of physical or chemical removal of the occluding thrombus. Published version |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|